Zhou Chong, Liu Qin, Meng Fanyan, Ding Naiqing, Yan Jing, Liu Baorui
The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China.
J Gastrointest Oncol. 2022 Oct;13(5):2249-2258. doi: 10.21037/jgo-22-951.
Radiation resistance remains the leading cause of radiotherapy (RT) failure. The development of tumor-specific targeted sensitizers is key to overcoming radiation resistance. Our early data showed that cancer cell penetration was simulated by internalizing arginine-glycine-aspartic acid (iRGD), and the irradiation efficacy was improved. The present study aims to design and fabricate iRGD-modified red blood cell (RBCs) for tumor targeting and RT enhancement, and to evaluate its safety and efficacy .
1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-poly ethylene glycol-iRGD (DSPE-PEG-iRGD) was used to modify RBCs by a lipid-insertion method without direct chemical bioconjugation. Fluorescent dyes were used to trace the functional RBCs through confocal microscopy examination. stability evaluation was performed using cell culture medium incubation for 48 h followed by fluorescence decay assay. Furthermore, a subcutaneous cancer cell mouse model was constructed with MKN-45 cells for target efficacy and RT enhancement evaluation with DSPE-PEG-iRGD-modified RBCs (RBC-iRGD).
Successful construction of RBC-iRGD was verified by the presence of the yellow fluorescence, and an approximately 10 iRGD molecules were labeled on a single RBC. The final RBC-iRGD showed good stability without any hemolytic effects in the cell culture medium. Moreover, higher fluorescence intensity and decreased liver and spleen accumulation could be observed in RBC-iRGD compared to RBC + iRGD . The RBC-iRGD exerted enhanced radiosensitivity in subcutaneous gastric tumor mice.
The RBC-iRGD exerted good tumor-targeting efficacy and favorable effects for RT enhancement .
辐射抗性仍然是放射治疗（RT）失败的主要原因。开发肿瘤特异性靶向增敏剂是克服辐射抗性的关键。我们早期的数据表明，通过内化精氨酸 - 甘氨酸 - 天冬氨酸（iRGD）可模拟癌细胞穿透，并且提高了照射效果。本研究旨在设计和制备用于肿瘤靶向和增强放疗的iRGD修饰红细胞（RBC），并评估其安全性和有效性。
采用脂质插入法，无需直接化学生物偶联，用1,2 - 二硬脂酰 - sn - 甘油 - 3 - 磷酸乙醇胺 - 聚乙二醇 - iRGD（DSPE - PEG - iRGD）修饰红细胞。使用荧光染料通过共聚焦显微镜检查追踪功能性红细胞。通过在细胞培养基中孵育48小时，然后进行荧光衰减测定来进行稳定性评估。此外，用MKN - 45细胞构建皮下癌细胞小鼠模型，以评估DSPE - PEG - iRGD修饰的红细胞（RBC - iRGD）的靶向疗效和放疗增强效果。
通过黄色荧光的存在验证了RBC - iRGD的成功构建，并且在单个红细胞上标记了约10个iRGD分子。最终的RBC - iRGD在细胞培养基中显示出良好的稳定性，没有任何溶血作用。此外，与RBC + iRGD相比，在RBC - iRGD中可观察到更高的荧光强度以及肝脏和脾脏积累的减少。RBC - iRGD在皮下胃癌小鼠中发挥了增强的放射敏感性。
RBC - iRGD具有良好的肿瘤靶向疗效和放疗增强效果。
